This invention relates to the synthesis of bromobiphenyls. In particular, it relates to such a synthesis from a phenylboronic acid.
Bromobiphenyls are useful intermediates for the production of agricultural chemicals, liquid crystals, and pharmaceuticals. For instance, 2-fluoro-4-bromobiphenyl is the key intermediate for the manufacture of flurbiprofen, a non-steroidal anti-inflammatory and analgesic compound.
N. Miyaura, et. al., The Palladium-Catalyzed Cross-Coupling Reaction of Phenylboronic Acid with Haloarenes in the Presence of Bases, Synthetic Communications, 11(7), 513-519 (1981), demonstrated the feasibility of synthesizing unsymmetrical biaryl compounds by the palladium catalyzed coupling of phenylboronic acid with haloarenes. In this reaction, bromobenzene reacted with phenylboronic acid to produce biphenyl in very good yields. Iodobenzene was less reactive, and chlorobenzene was not reactive. A variety of additional reagents such as p-chlorobromobenzene and p-dibromobenzene were also used successfully. The reactions were catalyzed with tetrakis(triphenylphosphine)palladium (Pd(PPh.sub.3).sub.4) and a base. The authors reported that the reaction would not proceed in any noticeable amount in the absence of a base, which was preferably 2 molar aqueous sodium carbonate.
R. Miller, et. al, Stoichiometric Synthesis of Unsymmetrical Mononitrobiphenyls via the Palladium-Catalyzed Cross-Coupling of Arylboronic Acids with Aryl Bromides, Organometallics, 1984, 3, 1261-1263, reported the reaction of phenylboronic acid (with and without various methyl substitutions) and o-, m-, and p-nitrobromobenzene to produce nitrobiphenyls. The reaction was also demonstrated with 3-nitrophenylboronic acid and bromoarenes. The general reported reaction scheme used tetrakis(triphenylphosphine)palladium (Pd(PPh.sub.3).sub.4) in the presence of aqueous sodium carbonate solution as the catalyst.
W. Thompson, et. al., A General Synthesis of 5-Arylnicotinates, J. Org. Chem.,1984, 49, 5237-5243; and M. Sharp, Synthetic Connections to the Aromatic Directed Metalation Reaction, Tetrahedron Letters. Vol. 28, No. 43, 5093-5096 (1987) both reported reactions and results that also show the reaction of bromobenzenes with phenylboronic acids using tetrakis(triphenylphosphine)palladium (Pd(PPh.sub.3).sub.4) in the presence of a base.